Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis

Background: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. Methods: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction (UPJO; n=321), ureterovesical junction obstruction/congenital megaureter (UVJO; n=178), and congenital hydronephrosis not otherwise specified (COU-NOS; n=234). We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders in 23 (3.1%) cases. No significant differences in the overall diagnostic yield among COU sub-phenotypes nor pathogenic SNVs in several genes were associated with any of the three categories. Discussion: Although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. However, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and genomic disorders suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. Conclusion: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.